Adaptive Mechanisms In GRown up ObeSity Study (AMIGROS)

Официальное название

Mechanistic Studies in Human Subcutaneous Adipose Tissue

Обзор

The investigator recently showed that the glycan-binding adipokine galectin-1 increased during overfeeding and that galectin-1 independently could predict type 2 diabetes. Further, the molecules that induce insulin release in the fasting state when blood glucose is normal remain elusive. It is possible that galectin-1 is involved in adaptive mechanisms in adipose tissue in obese subjects.

Подробное описание

The investigator will define adaptive mechanisms in adipose tissue associated with galectin-1 in obese insulin-sensitive (Ob-IS) subjects compared with obese insulin-resistant (Ob-IR) subjects and lean healthy controls. Further, the investigator will study molecules secreted from adipose tissue that might trigger insulin secretion when blood glucose is normal.

The investigator hypothesizes that Ob-IS subjects keep fatty acid levels normal through an adaptive response in adipose tissue that involves up-regulation of galectin-1 for dampening of immune cell activity and stimulation of lipolysis.

Вмешательства

• Устройство Subcutaneous microdialysis
  Group with Ob-IS participants, collection of abdominal subcutaneous interstitial dialysates after an overnight´s fast for later measurements of metabolites and peptides eg galectin-1. Group with Ob-IR participants, collection of abdominal subcutaneous interstitial dialysates after an overnight´s fast for later measurements of metabolites and peptides eg galectin-1. Group with Leans, collection of abdominal subcutaneous interstitial dialysates after an overnight´s fast for later measurements of

Первичные конечные точки

• Fasting galectin-1 concentration in subcutaneous interstitial fluid [Срок оценки: Three weeks]
• Fasting Neuropilin-1 concentration in subcutaneous interstitial fluid [Срок оценки: Three weeks]

Вторичные конечные точки (12)

• Fasting serum galectin-1 concentrations [Срок оценки: Three weeks]
• Fasting serum neuropilin-1 concentrations [Срок оценки: Three weeks]
• Fasting fatty acid levels in subcutaneous dialysates [Срок оценки: Three weeks]
• Fasting plasma fatty acid concentrations [Срок оценки: Three weeks]
• Fasting amino acid profile in subcutaneous dialysates [Срок оценки: Three weeks]
• Fasting serum amino acid concentrations [Срок оценки: Three weeks]
• Circulating metabolome including lipoprotein-related parameters measured by Mass Spectrometry [Срок оценки: Three weeks]
• Circulating lipidome including lipid derivatives measured by Mass Spectrometry [Срок оценки: Three weeks]
• Peptides identified by Mass Spectrometry in subcutaneous dialysates [Срок оценки: Three weeks]
• Ectopic lipid accumulation assessed by magnetic resonance imaging in relative measures [Срок оценки: Nine weeks]
• RNA sequencing results of subcutaneous adipose cells [Срок оценки: Six weeks]
• Function of immune cells in subcutaneous stromal vascular fraction characterized by Fluorescence Activated Cell Sorting (FACS) [Срок оценки: Six weeks]

Критерии участия

Критерии включения

• Men and women of age: 40.0 - 70.0 years
• BMI: 18.0 - 25.0 kg/m2 (lean subjects) and BMI 30.0 - 38.0 kg/m2 (Ob-IS and Ob-IR)
• Fasting insulin < 9.0 mU/l (lean and Ob-IS subjects) and fasting insulin > 9.0 mU/l (Ob-IR)
• Fasting glucose < 6.1 mmol/l
• Body temperature < 37.5°C
• First-degree relative with known T2D in Ob-IR
• Weight stable ± 5 kg < 3 months before screening
• Fluent in Swedish and can follow given instructions
• Consent given to participate

Критерии исключения

• First-degree relative with known T2D in lean or Ob-IS subjects
• Alcohol intake > 10 units/week or known high alcohol intake < 10 years back in time
• Daily use of cigarettes or daily frequent use of smokeless tobacco not enabling the participant to suspend nicotine during a visit at the research center without getting abstinent
• Regular physical activity corresponding to Saltin-Gimby level 4
• Special diet eg Atkins or 5:2 for weight reduction. Vegetarian food accepted if duration > 1 year
• Impaired fasting glucose (IFG) (venous fasting plasma glucose 6.1-6.9 mmol/l)
• Type 2 diabetes according to ADA criteria
• Ongoing or previous ischemic heart disease, eg angina pectoris, unstable angina or previous myocardial infarction treated with platelet inhibitors or non vitamin-K oral anticoagulants
• Heart failure (NYHA II-IV) or cardiac arrhytmia that needs medical treatment
• Previous cerebral infarction or transitory ischemic episodes (TIA) treated with platelet inhibitors or other anticoagulants
• Peripheral arterial insufficiency eg claudication
• Hypertension >170/105 mmHg at screening or more than one class of drugs for treatment of known hypertension
• Lipid disorder defined as fasting serum triglycerides > 5.0 mmol/l or serum cholesterol > 7.5 mmol/l
• Hematologic diseases such as anemia not being substituted (Hb < 130 g/l in males and Hv < 120 g/l in females) or disease causing bleeding disorder
• Renal failure defined as absolute estimated glomerular filtration rate (eGFRcreatinine) < 60 ml/min/1.73 m2
• Hypothyroidism defined as TSH > 4.0 mIE/l and symptoms
• Liver disease e.g. hepatitis B, cirrhosis or conditions where AST or ALT are > 2 times UNL
• Systemic inflammatory disease e.g. rheumatoid arthritis, ulcerative cholitis or Chrons disease. Celiac disease, dyspepsia or IBS are excepted
• Chronic bronchitis or chronic obstructive pulmonary with disease symptoms
• Previous pancreatitis or other disease in pancreas that needs treatment
• Migraine elicited by stress
• Spinal insufficiency causing inconvenience lying in supine position during the study day
• Drug addiction interfering with the study procedures
• Psychiatric insufficiency interfering with the study procedures
• Medication with potential to affect adipose tissue metabolism that can not be stopped 10 days before the study days
• Treatment with beta-blockers
• Less than three months from previous use of antibiotics
• Cancer disease < 5 years since diagnosis
• Physical examination or laboratory results indicating that participation in the study is inappropriate
• Pregnancy or intention to be pregnant during the study
• Shift work > 1 time per week that might interfere with the circadian rhytm
• Other reasons that causes the PI to believe that participation is inappropriate

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Модель наблюдения

Случай-контроль

Центры проведения

Швеция · 1 центр

• Gothia Forum CTC — Gothenburg

Публикации

• Fryk E, Sundelin JP, Strindberg L, Pereira MJ, Federici M, Marx N, Nystrom FH, Schmelz M, Svensson PA, Eriksson JW, Boren J, Jansson PA. Microdialysis and proteomics of subcutaneous interstitial fluid reveals increased galectin-1 in type 2 diabetes patients. Metabolism. 2016 Jul;65(7):998-1006. doi: 10.1016/j.metabol.2016.04.003. Epub 2016 Apr 13. PMID 27282870
• Drake I, Fryk E, Strindberg L, Lundqvist A, Rosengren AH, Groop L, Ahlqvist E, Boren J, Orho-Melander M, Jansson PA. The role of circulating galectin-1 in type 2 diabetes and chronic kidney disease: evidence from cross-sectional, longitudinal and Mendelian randomisation analyses. Diabetologia. 2022 Jan;65(1):128-139. doi: 10.1007/s00125-021-05594-1. Epub 2021 Nov 7. PMID 34743218
• Fryk E, Olausson J, Mossberg K, Strindberg L, Schmelz M, Brogren H, Gan LM, Piazza S, Provenzani A, Becattini B, Lind L, Solinas G, Jansson PA. Hyperinsulinemia and insulin resistance in the obese may develop as part of a homeostatic response to elevated free fatty acids: A mechanistic case-control and a population-based cohort study. EBioMedicine. 2021 Mar;65:103264. doi: 10.1016/j.ebiom.2021.103 PMID 33712379
• Fryk E, Silva VRR, Jansson PA. Galectin-1 in Obesity and Type 2 Diabetes. Metabolites. 2022 Sep 30;12(10):930. doi: 10.3390/metabo12100930. PMID 36295832

Идентификаторы

NCT: NCT06065930 · 2023-02051-02

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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